First published in The Crisis in 1921, "The Negro Speaks of Rivers", which became Hughes's signature poem, was collected in his first book of poetry The Weary Blues (1926). Hughes's life and work were enormously influential during the Harlem Renaissance of the 1920s, alongside those of his contemporaries, Zora Neale Hurston, Wallace Thurman, Claude McKay, Countee Cullen, Richard Bruce Nugent, and Aaron Douglas. Except for McKay, they worked together also to create the short-lived magazine Fire!! Devoted to Younger Negro Artists. Hughes, who claimed Paul Lawrence Dunbar, Carl Sandburg, and Walt Whitman as his primary influences, is particularly known for his insightful, colorful portrayals of black life in America from the twenties through the sixties. As one of the founders of the Harlem Renaissance, which he practically defined in his essay, "The Negro Artist and the Racial Mountain" (1926).

Langston was more than a poet, he was an activist as well. Hughes was unashamedly black at a time when blackness was démodé. He stressed the theme of "black is beautiful" as he explored the black human condition in a variety of depths. His main concern was the uplift of his people, whose strengths, resiliency, courage, and humor he wanted to record as part of the general American experience. His poetry and fiction portrayed the lives of the working class blacks in America, lives he portrayed as full of struggle, joy, laughter, and music. Permeating his work is pride in the African-American identity and its diverse culture. "My seeking has been to explain and illuminate the Negro condition in America and obliquely that of all human kind," Hughes is quoted as saying. He confronted racial stereotypes, protested social conditions, and expanded African America’s image of itself; a “people’s poet” who sought to reeducate both audience and artist by lifting the theory of the black aesthetic into reality. An expression of this is this poem:

"My People" picture book by Charles R. Smith

"My People"

by Langston Hughes

The night is beautiful,

So the faces of my people.

The stars are beautiful,

So the eyes of my people

Beautiful, also, is the sun.

Beautiful, also, are the souls of my people.

In 1932, Hughes became part of a group of black people who went to the Soviet Union to make a film depicting the plight of African Americans in the United States. The film was never made, but Hughes was given the opportunity to travel extensively through the Soviet Union and to the Soviet-controlled regions in Central Asia, the latter parts usually closed to Westerners. While there, he met African-American Robert Robinson, living in Moscow and unable to leave. In Turkmenistan, Hughes met and befriended the Hungarian polymath Arthur Koestler. Hughes also managed to travel to China and Japan before returning to the States.

Partly as a show of support for the Republican faction during the Spanish Civil War, in 1937 Hughes traveled to Spain as a correspondent for the Baltimore Afro-American and other various African-American newspapers. Hughes initially did not favor black American involvement in the war because of the persistence of discriminatory U.S. Jim Crow laws existing while blacks were encouraged to fight against Fascism and the Axis powers. He came to support the war effort and black American involvement in it after deciding that blacks would also be contributing to their struggle for civil rights at home. When asked why he never joined the Communist Party, he wrote "it was based on strict discipline and the acceptance of directives that I, as a writer, did not wish to accept." In 1953, he was called before the Senate Permanent Subcommittee on Investigations led by Senator Joseph McCarthy.

In addition to leaving us a large body of poetic work, Hughes wrote eleven plays and countless works of prose, including the well-known “Simple” books: Simple Speaks His Mind, Simple Stakes a Claim,Simple Takes a Wife, and Simple's Uncle Sam. He edited the anthologies The Poetry of the Negro and The Book of Negro Folklore, wrote an acclaimed autobiography (The Big Sea) and co-wrote the play Mule Bone with Zora Neale Hurston.

In his memory, his residence at 20 East 127th Street in Harlem, New York City, has been given landmark status by the New York City Preservation Commission, and East 127th Street has been renamed "Langston Hughes Place."